Shigeki Nishimori
Harvard University
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Publication
Featured researches published by Shigeki Nishimori.
Journal of Biological Chemistry | 2003
Tomotaka Yokoo; Hideo Toyoshima; Mitsuhiro Miura; Yuhui Wang; Kaoruko Iida; Hiroaki Suzuki; Hirohito Sone; Hitoshi Shimano; Takanari Gotoda; Shigeki Nishimori; Keiji Tanaka; Nobuhiro Yamada
p57Kip2 is the only cyclin-dependent kinase (Cdk) inhibitor shown to be essential for mouse embryogenesis. The fact suggests that p57 has a specific role that cannot be compensated by other Cdk inhibitors. LIM-kinase 1 (LIMK-1) is a downstream effector of the Rho family of GTPases that phosphorylates and inactivates an actin depolymerization factor, cofilin, to induce the formation of actin fiber. Here we demonstrate that p57 regulates actin dynamics by binding and translocating LIMK-1 from the cytoplasm into the nucleus, which in turn results in a reorganization of actin fiber. The central region of p57, a unique feature among the Cdk inhibitors, and the N-terminal region of LIMK-1, which contains the LIM domains were essential for the interaction. Expression of p57, but not p27Kip1 or a p57 mutant, with a deletion in the central region was shown to induce marked reorganization of actin filament and a translocation of LIMK-1. Our findings indicate p57 may act as a key regulator in embryogenesis by bearing two distinct functions, the regulation of cell cycle through binding to Cdks and the regulation of actin dynamics through binding to LIMK-1, both of which should be important in developmental procedure.
Journal of Bone and Mineral Research | 2015
Marc N. Wein; Jordan Spatz; Shigeki Nishimori; John G. Doench; David E. Root; Philip Babij; Kenichi Nagano; Roland Baron; Daniel J. Brooks; Mary L. Bouxsein; Paola Divieti Pajevic; Henry M. Kronenberg
Osteocytes secrete paracrine factors that regulate the balance between bone formation and destruction. Among these molecules, sclerostin (encoded by the gene SOST) inhibits osteoblastic bone formation and is an osteoporosis drug target. The molecular mechanisms underlying SOST expression remain largely unexplored. Here, we report that histone deacetylase 5 (HDAC5) negatively regulates sclerostin levels in osteocytes in vitro and in vivo. HDAC5 shRNA increases, whereas HDAC5 overexpression decreases SOST expression in the novel murine Ocy454 osteocytic cell line. HDAC5 knockout mice show increased levels of SOST mRNA, more sclerostin‐positive osteocytes, decreased Wnt activity, low trabecular bone density, and reduced bone formation by osteoblasts. In osteocytes, HDAC5 binds and inhibits the function of MEF2C, a crucial transcription factor for SOST expression. Using chromatin immunoprecipitation, we have mapped endogenous MEF2C binding in the SOST gene to a distal intergenic enhancer 45 kB downstream from the transcription start site. HDAC5 deficiency increases SOST enhancer MEF2C chromatin association and H3K27 acetylation and decreases recruitment of corepressors NCoR and HDAC3. HDAC5 associates with and regulates the transcriptional activity of this enhancer, suggesting direct regulation of SOST gene expression by HDAC5 in osteocytes. Finally, increased sclerostin production achieved by HDAC5 shRNA is abrogated by simultaneous knockdown of MEF2C, indicating that MEF2C is a major target of HDAC5 in osteocytes.
EMBO Reports | 2008
Minsoo Kim; Takashi Nakamoto; Shigeki Nishimori; Keiji Tanaka; Tomoki Chiba
Transforming growth factor‐β1 (TGF‐β1) has many physiological functions and inhibits the differentiation of osteoblasts. Previously, we reported that TGF‐β1 stimulation induces the degradation of p57KIP2 in osteoblasts. p57KIP2 proteolysis depends on the ubiquitin–proteasome pathway and SMAD‐mediated transcription; however, the molecular mechanism underlying p57KIP2 degradation has been largely unknown. Here, we show that FBL12, a new F‐box protein expressed in the limb bud of developing embryos, is involved in TGF‐β1‐induced degradation of p57KIP2. FBL12 formed an SCFFBL12 complex and directly ubiquitinated p57KIP2 in a phosphorylation‐dependent manner. Inhibition of FBL12 by RNA interference suppressed the degradation of p57KIP2 and a dominant‐negative mutant of FBL12 (FBL12ΔF) increased the steady‐state level of p57KIP2. Furthermore, wild‐type FBL12 inhibited and FBL12ΔF promoted the differentiation of primary osteoblasts. As overexpression of p57KIP2 promoted osteoblast differentiation, these results indicate the importance of FBL12 and the degradation of p57KIP2 in the regulation of osteoblast cell differentiation.
Nature Communications | 2016
Marc N. Wein; Yanke Liang; Olga Göransson; Thomas B. Sundberg; Jinhua Wang; Elizabeth A. Williams; Maureen J. O'Meara; Nicolas Govea; Belinda Beqo; Shigeki Nishimori; Kenichi Nagano; Daniel J. Brooks; Janaina S. Martins; Braden Corbin; Anthony Anselmo; Ruslan I. Sadreyev; Joy Y. Wu; Kei Sakamoto; Marc Foretz; Ramnik J. Xavier; Roland Baron; Mary L. Bouxsein; Thomas J. Gardella; Paola Divieti-Pajevic; Nathanael S. Gray; Henry M. Kronenberg
Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.
Journal of Bone and Mineral Research | 2015
Garyfallia Papaioannou; Fatemeh Mirzamohammadi; Thomas S. Lisse; Shigeki Nishimori; Marc N. Wein; Tatsuya Kobayashi
Growth plate chondrocytes go through multiple differentiation steps and eventually become hypertrophic chondrocytes. The parathyroid hormone (PTH)‐related peptide (PTHrP) signaling pathway plays a central role in regulation of hypertrophic differentiation, at least in part, through enhancing activity of histone deacetylase 4 (HDAC4), a negative regulator of MEF2 transcription factors that drive hypertrophy. We have previously shown that loss of the chondrocyte‐specific microRNA (miRNA), miR‐140, alters chondrocyte differentiation including mild acceleration of hypertrophic differentiation. Here, we provide evidence that miR‐140 interacts with the PTHrP‐HDAC4 pathway to control chondrocyte differentiation. Heterozygosity of PTHrP or HDAC4 substantially impaired animal growth in miR‐140 deficiency, whereas these mutations had no effect in the presence of miR‐140. miR‐140–deficient chondrocytes showed increased MEF2C expression with normal levels of total and phosphorylated HDAC4, indicating that the miR‐140 pathway merges with the PTHrP‐HDAC4 pathway at the level of MEF2C. miR‐140 negatively regulated p38 mitogen‐activated protein kinase (MAPK) signaling, and inhibition of p38 MAPK signaling reduced MEF2C expression. These results demonstrate that miR‐140 ensures the robustness of the PTHrP/HDAC4 regulatory system by suppressing MEF2C‐inducing stimuli.
Biochemical and Biophysical Research Communications | 2003
Tomoki Okazaki; Shigeki Nishimori; Etsuro Ogata; Toshiro Fujita
The mechanism of transcriptional repression by nuclear hormone receptors, especially in the presence of the ligands, is largely unknown. We previously reported that 1,25-dihydroxyvitamin D(3) (1,25 vitamin D3) inhibited expression of the parathyroid hormone-related polypeptide (PTHrP) gene through the interaction between the liganded monomeric vitamin D receptor (VDR) and the negative DNA element in the PTHrP gene (nVDRE(RP)). In this study, we employed chromatin immunoprecipitation (ChIP) assay and confirmed that 1,25 vitamin D3 recruited DNA-dependent protein kinase (DNA-PKcs) to the chromatinized nVDRE(RP). Conversely, the regulatory subunits of DNA-PK were associated with the nVDRE(RP) sequences only when 1,25 vitamin D3 was absent. VDR was constitutively associated with these chromatinized nVDRE(RP) sequences. Furthermore, DNA-PKcs could phosphorylate VDR in vitro. We raise a possibility that a conformational change of VDR through its phosphorylation mediated by DNA-PKcs underlies the mechanism of gene repression by 1,25 vitamin D3-bound VDR.
Developmental Biology | 2009
K.L. Conen; Shigeki Nishimori; S. Provot; Henry M. Kronenberg
Lbh is thought to act as a transcriptional cofactor and is highly conserved among species. Here we show that Lbh is expressed in chondrocytes, cells of the perichondrium, and the primary spongiosa in fetal growth plates of mice and chickens. Lbh overexpression in chick wings, using the RCAS-retroviral vector strategy, results in shortened skeletal elements and delayed hypertrophic chondrocyte maturation and bone formation. Additionally, osteoclast and endothelial cell invasion are delayed in the Lbh-overexpressing bones. Finally, we find a dramatic suppression of Runx2 and VEGF mRNAs in chondrocytes and osteoblasts that overexpress Lbh. Strikingly, this abnormal bone development in infected limbs can be rescued by concurrent overexpression of Runx2. These results suggest that during endochondral bone formation, Lbh may negatively regulate vascular invasion and formation of the early ossification center at least in part by interfering with Runx2 and/or VEGF expression.
Journal of Biological Chemistry | 1997
Tomoki Okazaki; Toshio Ishikawa; Shigeki Nishimori; Tetsuya Igarashi; Keishi Hata; Toshiro Fujita
The negative calcium responsive elements of the parathyroid hormone gene bind to a specific set of nuclear proteins in an extracellular calcium (Ca2+ e )-dependent manner. We have found that one of the negative calcium responsive elements, named oligo B, is found in the 5′-flanking region of such vasoactive genes as the vasopressin and atrial natriuretic polypeptide genes. Furthermore, the oligo B-like sequence in the former gene is conserved throughout evolution. Because expression of some of these vasoactive genes is altered by external stimuli which change cell volume, we examined whether oligo B is involved in gene regulation by hyperosmolarity. Here, we demonstrate that the binding between oligo B and its binding nuclear proteins including a redox factor 1 was reduced by hyperosmolarity generated by sodium chloride but not by urea. Such attenuated binding was reversed by dephosphorylating nuclear proteins by a potato acid phosphatase, suggesting that NaCl treatment elicited phosphorylation of these nuclear proteins to weaken their binding activity to oligo B. Furthermore, these nuclear events led to hyperosmolarity-mediated transcriptional stimulation of the genes bearing this DNA element in the cultured cells.
Nature Communications | 2016
Wanida Ono; Naoko Sakagami; Shigeki Nishimori; Noriaki Ono; Henry M. Kronenberg
Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP–PPR system during root morphogenesis and tooth eruption.
Endocrinology | 2015
Takao Hirai; Tatsuya Kobayashi; Shigeki Nishimori; Andrew C. Karaplis; David Goltzman; Henry M. Kronenberg
The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone-specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis. We found that the fetal calcium concentration of Runx2 KO mice was significantly higher than that of control littermates, suggesting that calcium flux into bone had a considerable influence on the circulating calcium concentration. Moreover, Runx2:PTH double mutant fetuses showed calcium levels similar to those of Runx2 KO mice, suggesting that part of the fetal hypocalcemia in PTH KO mice was caused by the increment of the mineralized bone mass allowed by the formation of osteoblasts. Finally, Rank:PTH double mutant mice had a blood calcium concentration even lower than that of the either Rank KO or PTH KO mice alone at embryonic day 18.5. These observations in our genetic models suggest that PTH/PTHrP receptor signaling in bones has a significant role of the regulation of fetal blood calcium concentration and that both placental transport and osteoclast activation contribute to PTHs hypercalcemic action. They also show that PTH-independent deposition of calcium in bone is the major controller of fetal blood calcium level.